SUMMARY Multiple recent studies have provided proof-of-concept that a ?functional cure? of HIV-1 infection, i.e. long-term control of HIV without continued treatment, is achievable. The VISCONTI study identified 14 HIV+ patients, who received antiretroviral treatment (ART) during primary HIV-1 infection, and maintained post-treatment control of their virus below the limit of detection for a median of 89 months after stopping therapy. Persaud et al. described a HIV-1 infected infant who started ART within 30 hours after birth, discontinued therapy at 18 months of age, then remained undetectable, off-therapy, for 27 months before the virus rebounded. A recent study showed that SIV-infected macaques on ART given an antibody (Ab) against the integrin ?4?7 could maintain undetectable plasma viremia for over 9 months after all treatment was stopped. Finally, treatment with broadly neutralizing Abs (bnAbs) in some macaques infected with SIV also led to virological control for an extended period even after completion of Ab treatment. To realize the promise of these advances, we need a better understanding of the factors that lead to establishment of undetectable or controlled viral loads in the absence of treatment. Here we propose to develop a set of new models to help understand how functional cure was obtained in the studies mentioned above and to understand more generally under what conditions and interventions functional cure can be achieved. To this end, we will collaborate with leading experimental scientists, who will provide novel datasets that will allow us to fulfil the following specific aims. Aim 1. Determine the mechanisms of action of HIV-1 specific bnAbs in vivo. We will develop new models of antibody action, incorporating multiple biological functions, to explain experiments of bnAbs infusions in HIV-infected humans and SIV-infected macaques. These models will help determine the main mechanisms of action of bnAbs. Aim 2. Determine whether treatment with monoclonal antibodies can lead to a change in viral load set-point. We will develop models with multiple stable steady states of viral load (high and low levels) driven by the interplay between immune responses and the establishment of the latent reservoir. These models will be calibrated by experimental data in humans and in the macaque model of SIV and will provide a mechanistic picture of the effects of these antibodies. Aim 3. Determine the within host dynamics of Zika virus infection and predict the effects of therapy. We will leverage the work in the previous aims to develop models for this emerging infection and study the effects of different therapies, including antibodies, in controlling Zika virus.